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Biomedical subjects

Nobuyuki Takasu

Publications and source records attributed to Nobuyuki Takasu.

At least 37 records · Page 2Linked to original sources
PubMed2005

Electrophysiologic characteristics of atrial myocytes in levo-thyroxine-treated rats.

To investigate whether thyroid hormone modulates electrical properties of atrial myocytes, electrocardiogram (ECG), action potentials (APs), and ionic currents were measured. Male Sprague-Dawley rats were randomly divided into control and levo-thyroxine (T4)-treated groups at 6 weeks of age. Levo-thyroxine (500 microg/kg of body weight) was injected daily into the peritoneal cavity for 14 days (T4-treated rats) and the same volume of saline was injected in control rats daily. ECG signals were recorded using apex-base leads. APs, voltage-dependent Na+ and L-type Ca2+ channel current (I(Na) and I(Ca(L))), inwardly rectifying K+ channel current (I(K1)), transient outward K+ channel current (I(to)), and delayed rectifier K+ channel current (I(K(delay))) were measured using patch-clamp techniques. T4 treatment significantly changed electrical properties in rat atrial myocytes, including (1) the increase in heart rate, (2) the increase in cell size, (3) the shortening of action potential duration (APD), (4) the increase in cell membrane capacitance (C(m)), and (5) the decrease in input resistance (R(in)). Although the current densities of I(Na) and I(K1) in T4-treated atrial myocytes did not differ from those in control cells, I(Ca(L)) was significantly decreased and I(K(delay)) was significantly increased in T4-treated rats. Thus, thyrotoxicosis could induce the shortening of APD by alterations in current density of both I(Ca(L)) and I(K(delay)) in rat atrial myocytes.

Action Potentials↗
PubMed2005

Effect of sodium channel blocker, pilsicainide hydrochloride, on net inward current of atrial myocytes in thyroid hormone toxicosis rats.

To investigate effect of pilsicainide hydrochloride (pilsicainide) on electrocardiogram (ECG) signals and action potentials (APs) of atrial myocytes, levo-thyroxine (T4, 500 microg/kg body weight) was daily injected into peritoneal cavity of Sprague-Dawley rats for 14 days. T4-treatment significantly shortened RR interval, P wave, and QRS complex durations on ECG. Although pilsicainide did not affect the heart rate, P wave and corrected QT interval (QTc) was increased in T4-treated rats. AP recordings revealed that AP durations at 20%, 50%, and 90% repolarization were significantly shortened and maximal rate of rise (Max dV/dt) was significantly increased in T4-treated rat atrial cells. Pilsicainide significantly decreased AP amplitude (APA) and Max dV/dt in both control and T4-treated rat atrial cells. Concentration-inhibition study demonstrated that pilsicainide significantly inhibited net inward current of T4-treated rats at lower concentration (IC50 of 29.2 microg/mL) than that of control rats (133 microg/mL). In conclusion, pilsicainide could decrease the conduction velocity in T4-treated rat atrium by decreasing the Max dV/dt and net inward current, which could be a possible treatment of thyrotoxicosis-induced arrhythmia.

Action Potentials↗
PubMed2005

Resistance to Apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis and constitutive expression of Apo2L/TRAIL in human T-cell leukemia virus type 1-infected T-cell lines.

Adult T-cell leukemia (ATL), a CD4+-T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1), is difficult to cure, and novel treatments are urgently needed. Apo2 ligand (Apo2L; also tumor necrosis factor-related apoptosis-inducing ligand [TRAIL]) has been implicated in antitumor therapy. We found that HTLV-1-infected T-cell lines and primary ATL cells were more resistant to Apo2L-induced apoptosis than uninfected cells. Interestingly, HTLV-1-infected T-cell lines and primary ATL cells constitutively expressed Apo2L mRNA. Inducible expression of the viral oncoprotein Tax in a T-cell line up-regulated Apo2L mRNA. Analysis of the Apo2L promoter revealed that this gene is activated by Tax via the activation of NF-kappaB. The sensitivity to Apo2L was not correlated with expression levels of Apo2L receptors, intracellular regulators of apoptosis (FLICE-inhibitory protein and active Akt). NF-kappaB plays a crucial role in the pathogenesis and survival of ATL cells. The resistance to Apo2L-induced apoptosis was reversed by N-acetyl-L-leucinyl-L-leucinyl-lLnorleucinal (LLnL), an NF-kappaB inhibitor. LLnL significantly induced the Apo2L receptors DR4 and DR5. Our results suggest that the constitutive activation of NF-kappaB is essential for Apo2L gene induction and protection against Apo2L-induced apoptosis and that suppression of NF-kappaB may be a useful adjunct in clinical use of Apo2L against ATL.

Apoptosis↗
PubMed2005

Fucoidan extracted from Cladosiphon okamuranus Tokida induces apoptosis of human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells.

Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1) and remains incurable. The highest endemic area of HTLV-1 carriers in Japan is located in Okinawa, and novel treatments are urgently needed in this area. We extracted fucoidan, a sulfated polysaccharide, from the brown seaweed Cladosiphon okamuranus Tokida cultivated in Okinawa, Japan and examined its tumor-suppression activity against ATL. Fucoidan significantly inhibited the growth of peripheral blood mononuclear cells of ATL patients and HTLV-1-infected T-cell lines but not that of normal peripheral blood mononuclear cells. Fucoidan induced apoptosis of HTLV-1-infected T-cell lines mediated through downregulation of cellular inhibitor of apoptosis protein-2 and survivin and G1 phase accumulation through the downregulation of cyclin D2, c-myc, and hyperphosphorylated form of the retinoblastoma tumor suppressor protein. Further analysis showed that fucoidan inactivated NF-kappaB and activator protein-1 and inhibited NF-kappaB-inducible chemokine, C-C chemokine ligand 5 (regulated on activation, normal T expressed and secreted) production, and homotypic cell-cell adhesion of HTLV-1-infected T-cell lines. In vivo use of fucoidan resulted in partial inhibition of growth of tumors of an HTLV-1-infected T-cell line transplanted subcutaneously in severe combined immune deficient mice. Our results indicate that fucoidan is a potentially useful therapeutic agent for patients with ATL.

Animals↗
PubMed2004

Restricted expression of tumor necrosis factor-related apoptosis-inducing ligand receptor 4 in human peripheral blood lymphocytes.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in tumor but not normal cells, thus providing therapeutic possibilities for human cancers. However, it is not fully clear how widespread TRAIL receptors are, or how TRAIL signaling is modulated in normal cells. We characterized cell surface expression of TRAIL receptors in normal healthy donor peripheral blood and report that each of the TRAIL receptors are characteristically expressed on restricted cell populations. TRAIL-R1 is distinctively expressed on B-lymphocytes, TRAIL-R2 on monocytes, TRAIL-R3 on neutrophils and most impressively, CD8+ lymphocytes and NKT lymphocytes but not CD4+ lymphocytes express TRAIL-R4.

Cells, Cultured↗
PubMed2004

Genome-wide linkage analysis of type 2 diabetes mellitus reconfirms the susceptibility locus on 11p13-p12 in Japanese.

Type 2 diabetes mellitus is a heterogeneous disorder, and the development of type 2 diabetes mellitus is associated with both insulin secretion defect and insulin resistance. The primary metabolic defect leading to type 2 diabetes mellitus has been thought to be varied among populations, especially in Japanese and Caucasians. Here, we have done the genome-wide scan for type 2 diabetes mellitus using 102 affected Japanese sib-pairs to identify the genetic factors predisposing to type 2 diabetes mellitus. Nonparametric linkage analysis showed one suggestive evidence for linkage to 11p13-p12 [D11S905: two-point maximum LOD score (MLS) of 2.89 and multipoint MLS of 2.32] and one nominally significant evidence for linkage to 6q15-q16 (D6S462: two-point MLS of 2.02). Interestingly, the 11p13-p12 region was reported to be a susceptibility locus for Japanese type 2 diabetes mellitus with suggestive evidence of linkage, and D11S905 was within 5 cM to D11S935 with the highest MLS in the previous linkage analysis reported. The only overlapped susceptibility region with suggestive evidence of linkage for Japanese type 2 diabetes mellitus was D11S935-D11S905 among the three reports including this study. These results taken together suggest that a susceptibility gene for type 2 diabetes mellitus in Japanese will reside in 11p13-p12.

Chromosomes, Human, Pair 11↗
PubMed2004

Fluvastatin improves endothelial dysfunction in overweight postmenopausal women through small dense low-density lipoprotein reduction.

Small dense low-density lipoprotein (sdLDL), which are often associated with obesity, are considered as the most atherogenic and have been shown to impair endothelial function. It is not known whether reduction of sdLDL by pharmacological intervention can improve endothelial function. Thirty-four consecutive postmenopausal women with >/=5.70 mmol/L total cholesterol were placed into either an overweight (body mass index [BMI] >/= 25.0, n = 22) or a normal-weight (BMI < 25.0, n = 12) group, and forearm blood flow (FBF) was measured using strain-gauge plethysmography during reactive hyperemia before and after fluvastatin treatment. At baseline, the peak FBF during reactive hyperemia in the overweight group was less than that in the normal-weight group (mean +/- SD, 13.6 +/- 4.4 v 22.2 +/- 4.0 mL/min/100 mL, P <.01). The maximal FBF after nitroglycerin was similar in both groups. In the stepwise multiple regression analysis, only the concentration of sdLDL was the predictor for peak FBF (standard coefficient = -0.517, P =.0115). The nonsignificant parameters for the correlations in the model were age, BMI, systolic blood pressure, the homeostasis model assessment of insulin resistance (HOMA-IR), hemoglobin A(1c) (HbA(1c)), and LDL-cholesterol. Fluvastatin treatment was associated with the recovery of the peak FBF in the overweight group but it did not influence that of the normal-weight group. Changes in sdLDL fractions by fluvastatin correlated well with the peak FBF recovery. These results suggested that an increased sdLDL was linked to endothelial dysfunction in overweight postmenopausal women and fluvastatin treatment improved endothelial dysfunction by decreasing the atherogenic sdLDL fraction in this population.

Aged↗
PubMed2004

Cilostazol, a phosphodiesterase inhibitor, reduces microalbuminuria in the insulin-resistant Otsuka Long-Evans Tokushima Fatty rat.

We evaluated association between hyperinsulinemia/insulin resistance and microalbuminuria in the insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rat. OLETF rats showed glomerular hyperfiltration (an increase in creatinine clearance and a decrease in fractional excretion of Na) and microalbuminuria at the insulin-resistant prediabetic stage, and both were related to expression of transforming growth factor (TGF)-beta(1) and extracellular matrix protein such as fibronectin and collagen (a(1)) IV. Cilostazol, a selective type III cyclic nucleotide phosphodiesterase (PDE) inhibitor, normalized glomerular hyperfiltration and microalbuminuria with a parallel decline of TGF-beta(1) and extracellular matrix protein mRNA expression. Cilostazol may be beneficial to lessen early glomerular nephropathy in a state of hyperinsulinemia/insulin resistance.

Albuminuria↗
PubMed2004

Very late central nervous system relapse in a patient with B cell lymphoblastic lymphoma.

Very late relapse of lymphoblastic lymphoma (LBL) is very rare. We report a case of a patient who developed central nervous system (CNS) relapse of LBL 16 years after the onset of the primary disease. An 8-year-old girl was hospitalized with a skin tumor in the occipital region on November 27, 1984. Examination of a biopsy of the skin tumor showed typical features of non-Hodgkin's lymphoma (diffuse medium-sized cell type). She received multiagent chemotherapy and went into remission. On July 4, 2000, she was hospitalized with persistent headache. Cranial magnetic resonance imaging showed a cerebellar lesion, which was hypointense on T1-weighted images and of heterogeneous intensity on T2-weighted images. A midline suboccipital craniotomy was performed and pathological examination revealed a diffuse proliferation of lymphoid cells, which were positive for terminal deoxynucleotidyl transferase, but negative for CD45RO, CD3 and CD20. Tumor cells stained positively for CD10, CD22, CD38 and HLA-DR. Revised immunohistochemistry of the primary specimens of skin tumor obtained 16 years earlier revealed a phenotype similar to that of the CNS disease. Polymerase chain reaction products for the immunoglobulin gene from both the skin and cerebellar specimens were an identical size. Thus, the original diagnosis of diffuse medium-sized lymphoma was revised to B cell LBL. An isolated CNS relapse of LBL was apparent in the present case. After salvage chemotherapy, the patient underwent high-dose chemotherapy with autologous peripheral blood stem cell support and subsequent craniospinal irradiation. She went into a lasting complete remission.

Cell Proliferation↗
PubMed2003

PAX4 mutation (R121W) as a prodiabetic variant in Okinawans.

We previously reported that a missense mutation at codon 121 (CGG(Arg) to TGG(Trp), R121W) of PAX4 may be associated with the onset of type 2 diabetes in Japanese. In this study, we determined the frequency of the R121W mutation of PAX4 and characterized the prodiabetic phenotype in a population-based study. Healthy 372 residents participated in annual health check-ups in Nishihara (Okinawa, Japan) and unrelated 193 type 2 diabetic patients from the outpatient clinic of Ryukyu University Hospital were enrolled. Diagnosis of diabetes was based on the 1997 American Diabetes Association criteria. The R121W mutation in PAX4 was genotyped by PCR-RFLP analysis. In healthy residents, R121W mutation was detected in 12 of 372 residents (3.1%). The prevalence of newly diagnosed type 3 diabetes (25% vs. 5%, p=0.004) and HbA(1c) (5.6+/-1.9 vs. 5.1+/-0.7, p=0.026) was higher in the variants than in the wild-types. The odds ratio of diabetes in the R121W variants was 5.98 with 95% confidence interval from 1.50 to 23.9. The R121W mutation was observed in 12 of the 193 type 2 diabetic patients (6.2%). Onset-ages of diabetes were earlier (37+/-10 vs. 47+/-13 years, p=0.010) and the rate of insulin user was two times higher (83% vs. 41%, p=0.005) in the variants. The R121W mutation in PAX4 is a predisposing factor for the development of type 2 diabetes in Okinawans.

Aged↗